Carcinogenesis Advance Access originally published online on May 7, 2009
Carcinogenesis 2009 30(7):1139-1146; doi:10.1093/carcin/bgp116
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma
1 Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
2 Division of Digestive Surgery, Department of Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
3 Department of Genome Medicine, Hard Tissue Genome Research Center, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-ku, Tokyo 113-8510, Japan
4 Department of Basic Pathology, National Defense Medical College, 3-2 Namiki-chou Tokorozawa, Saitama 359-8513, Japan
5 Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
6 Department of Surgery, National Defense Medical College, 3-2 Namiki-chou Tokorozawa, Saitama 359-8513, Japan
7 Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-ku, Tokyo 113-8510, Japan
* To whom correspondence should be addressed. Tel: +81 03 5803 5820; Fax: +81 03 5803 0244; Email: johinaz.cgen{at}mri.tmd.ac.jp
Although we have identified two putative targets, ATF3 and CENPF, for a frequently gained/amplified region around 1q32–q41 in esophageal squamous cell carcinoma (ESCC), it is possible that other amplification targets remain to be identified. In this study, we tested whether SET and MYND domain-containing protein 2 (SMYD2), located between those two genes and encoding a lysine methyltransferase for histone H3K36 and p53K370 that regulates transcription and inhibits transactivation activity, respectively, acts as a cancer-promoting gene through activation/overexpression in ESCC. Frequent overexpression of SMYD2 messenger RNA and protein was observed in KYSE150 cells with remarkable amplification at 1q32–41.1 and other ESCC cell lines (11/43 lines, 25.6%). Overexpression of SMYD2 protein was frequently detected in primary tumor samples of ESCC (117/153 cases, 76.5%) as well and significantly correlated with gender, venous invasion, the pT category in the tumor–lymph node–metastases classification and status of recurrence. Patients with SMYD2-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors, and SMYD2 positivity was independently associated with a worse outcome in the multivariate analysis. Knockdown of SMYD2 expression inhibited and ectopic overexpression of SMYD2 promoted the proliferation of ESCC cells in a TP53 mutation-independent but SMYD2 expression-dependent manner. These findings suggest that SMYD2 plays an important role in tumor cell proliferation through its activation/overexpression and highlight its usefulness as a prognosticator and potential therapeutic target in ESCC.
Abbreviations: BAC, bacterial artificial chromosome; ESCC, esophageal squamous cell carcinoma; FACS, fluorescence-activated cell sorting; MD, methylation defective; mRNA, messenger RNA; RT–PCR, reverse transcription–polymerase chain reaction; siRNA, small interfering RNA; SMYD2, SET and MYND domain-containing protein 2; TNM, tumor–lymph node–metastases
Received February 15, 2009; revised April 23, 2009; accepted May 2, 2009.